Moxifloxacin hydrochloride compounds and intermediates and methods for making same

ABSTRACT

Methods for producing moxifloxacin hydrochloride compounds having very low levels of impurities are provided. Compounds produced using such methods and pharmaceutical compositions including such compounds are also provided.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No. 13/543,896filed Jul. 9, 2012 which claims benefit of Italian Patent ApplicationNo. TO2011A000705 filed Jul. 29, 2011, the contents of which areincorporated by reference in their entirety. To the extent appropriate,a claim of priority is made to each of the above disclosed applications.

FIELD OF THE INVENTION

The present invention relates to the pharmaceutically active ingredientknown as moxifloxacin hydrochloride and intermediates thereof.

BACKGROUND OF THE INVENTION

Moxifloxacin is a broad-spectrum fluoroquinolonic antibacterial agent,used for the treatment of respiratory infections (pneumonia, chronicsinusitis, chronic bronchitis) sold in form of hydrochloride by Bayer AGunder the name of Avelox® and Avalox®. It is also sold by Alcon Inc. ina low dosage form for ophthalmic use under the name of Vigamox®.

Moxifloxacin, of formula (II) and having the chemical name of3-quinolinecarboxylic,1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrole[3,4-b]pyridine-6-yl]-4-oxo-acid,is characterized by a fluoroquinolonic skeleton, which is common to thatof two other antibiotics of the same category (Gatifloxacin andBalofloxacin) and by a side chain constituted by(4aS,7aS)-octahydro-1H-pyrrole[3,4-b]pyridine.

The fluoroquinolonic intermediate of formula (V), with the 8-methoxygroup is a commercial product.

(4aS, 7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine, also referred to as(S,S)-2.8-Diazabycyclo[4.3.0]nonane and having CAS RN [151213-40-0] andformula (VI),

constitutes the side chain of moxifloxacin, is the key intermediate ofthe synthesis in that it has two chiral centers, both having an Sconfiguration, and is optically active and levogyre. The preparation ofthis key intermediate is also described in patent applicationsMI2009A001353 and WO2010/100215 both owned by F.I.S. Fabbrica ItalianaSintetici S.p.A. These references provide, respectively, for a processfor optimising the optical resolution and a regio and stereoselectivesynthesis process of the bioenzymatic type.

A first synthesis process of moxifloxacin hydrochloride described in EP550903 includes the coupling reaction between the1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acidof formula (V):

with the (4aS, 7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine intermediate offormula (VI) in the presence of a base:

Due to the low regioselectivity of the reaction, the product obtainedcontains the 6-isomer impurity of formula (VIII):

as greater impurity, which—being a position isomer—is difficult toseparate from the product, without significantly reducing its yield.

Chromatographic purification on a silica gel column leads to similarlylow yields.

WO 2008/138759 describes a process for the preparation of moxifloxacinhydrochloride monohydrate where the coupling reaction between1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acidof formula (V) with (S,S)-2.8-diazabycyclo[4.3.0]nonane of formula (VI)is carried out in the absence of a base and moxifloxacin is isolated asL-tartrate or fumarate or p-ditoluoyltartrate with the aim of purifyingit from the greater impurity, i.e. the 6-isomer of formula (VIII). It isthen converted into moxifloxacin hydrochloride.

Another synthesis process of moxifloxacin is described in WO 2005/012285includes the reaction between the ethyl ester of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acidof formula (IX):

with boric acid and acetic anhydride to form an intermediate boratecomplex with 95% yield which is then reacted with (4aS,7as)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) with 72% yield.After this the ester and the complex are hydrolysed, and salification iscarried out to give moxifloxacin hydrochloride with a 91% yield, for anoverall 62% molar yield.

In WO 2008/059223 a process similar to the previous one is employedexcept that the complex is generated using boric acid and propionicanhydride instead of acetic anhydride.

A fourth process, described in WO 2006/134491, provides for the reactionof 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinicacid of formula (V) with boron trifluoride etherate to provide adifluoroborate intermediate which is reacted with(S,S)-2.8-diazabycyclo[4.3.0]nonane of formula (VI) in presence of abase with a 92% yield providing a difluoroborate complex of moxifloxacinwhich is then hydrolized and salified to provide moxifloxacinhydrochloride with an overall yield ranging from 42 to 55%.

In addition, the synthesis of moxifloxacin has been conducted, asdescribed in EP 1832587, through a process similar to the previous one,carried out via a one-pot method and including silanization beforecomplexation through boron trifluoride.

The processes described above lead to unsatisfactory yields and requirethe use of toxic reagents such as boron trifluoride.

An alternative process which overcomes these problems and especiallythat of the 6-isomer impurity is described in the U.S. patentapplication Ser. No. 13/051,081 and Italian patent applicationMI2010A000450 both owned by F.I.S. Fabbrica Italiana Sintetici S.p.A.where magnesium salt is used for performing the coupling between the1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acidof formula (V) with the intermediate (4aS,7as)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) thus avoidingthe formation of the 6-isomer impurity of formula (VIII).

The above-described prior art processes for the preparation ofmoxifloxacin in their entirety require the use of coupling between thetwo syntons described previously. Such coupling also requires theinherent formation of another typical well known impurity ofmoxifloxacin referred to as 3-quinolinecarboxylic,1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-1-methyloctahydro-6H-pyrrole[3,4-b]pyridine-6-yl]-4-oxo-acid, having the formula (VII):

This impurity having the number CAS 721970-37-2 was identified andpublished for the first time by Dr. Reddy's Laboratories Ltd., BulkActives Unit-III, Hyderabad, AP (India) in the Journal of Pharmaceuticaland Biomedical Analysis (2004), 34(5), 1125-1129 where it is calledImpurity-1. It was observed to be present in amounts above 0.1% inindustrially produced moxifloxacin.

In the publication of the United States Pharmacopeia-India PrivateLimited (USP-India) on Chromatographia (2009), 69 (9-10), this impurityreferred to as Imp-1 was correctly defined as a process impurity. Thesamples used by USP-India to carry out the study were provided by Dr.Reddy's Laboratories Ltd. The developed HPLC method allows detectingsuch impurity in moxifloxacin with a 0.016% detectability limit.

This reference as well as our own experimentation confirm that theimpurity of formula (VII) is a typical process impurity of moxifloxacin.Its formation appears to be due to the action of hydrofluoric acid,released during the coupling of the two syntons on the methoxy group inposition 8 which releases the methyl carbocation which in turn alkylatesa second moxifloxacin molecule. This impurity is particularly difficultto remove from the product using conventional re-crystallizationmethods.

SUMMARY OF THE INVENTION

The present invention provides methods for the preparation ofmoxifloxacin hydrochloride having unexpected and surprisingly low levelsof the impurity 3-quinolinecarboxylic,1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-1-methyloctahydro-6H-pyrrole[3,4-b]pyridine-6-yl]-4-oxo-acid(formula (VII)).

Further characteristics and advantages of the methods and compositionsaccording to the present invention will be apparent from the descriptionoutlined below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a representative synthesis scheme of moxifloxacinhydrochloride according to the present invention.

FIG. 2 illustrates a 1H-NMR spectrum of moxifloxacin tosylate accordingthe present invention.

FIG. 3 illustrates a 1H-NMR spectrum of the impurity of moxifloxacin offormula VII).

FIG. 4 shows the X-Ray Powder Diffraction (XPRD) difractogram ofmoxifloxacin tosylate including parameters of the analysis.

FIG. 5 shows the FT-IR spectrum of moxifloxacin tosylate.

FIG. 6 shows a Differential Scanning calorimetry (DSC) curve ofmoxifloxacin tosylate.

FIG. 7 shows an image acquired with an optical microscope ofmoxifloxacin tosylate crystal powder.

DETAILED DESCRIPTION

The present invention provides novel methods for the preparation ofmoxifloxacin hydrochloride of formula (I):

comprising the following steps:

-   -   (a) salification of base moxifloxacin of formula (II):

-   -   -   with a sulfonic acid of formula (III):

R—SO₃H  (III)

wherein R is a C1-C12 linear or branched alkyl or an aryl, to provide acompound of formula (IV):

-   -   (b) optional purification of the compound of formula (IV), and    -   (c) conversion of the compound of formula (IV) into moxifloxacin        hydrochloride of formula (I).

It was discovered that preparing the salts of moxifloxacin with sulfonicacids alone results in moxifloxacin and salts thereof havingsurprisingly and unexpectedly low levels of the impurity of formula(VII).

As described herein the other methods of preparation of moxifloxacinsalts do not allow purifying the product from the impurity of formula(VII) equivalent to the compound salts of formula (IV) of the presentinvention, i.e. using the moxifloxacin salts with sulfonic acids. Thepreparation of some moxifloxacin salts different from the sulfonic acidsrevealed that the amount of such impurity is even increased thusconfirming the insolubility of such impurity with respect tomoxifloxacin itself.

The quantification in percentage area of the formula (VII) impuritycontent in moxifloxacin and salts thereof may be carried out through theHPLC method indicated in Example 5.

The residue R of the sulfonic acid used according to the process of theinvention is a C1-C12 linear or branched alkyl or an aryl. In particularR alkyl may be a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, docecyl and it may be linear or branched.R may thus also be isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl,n-pentyl, isopentyl, etc. In particular R aryl may be phenyl, tolyl(p-methylphenyl), xylyl, benzyl, naphthyl, indolyl, nosyl, etc.

In certain embodiments, R is selected from among C1-C4 alkyl, phenyl andtolyl. In other embodiments R is methyl or ethyl or tolyl. Thus,moxifloxacin mesylate or moxifloxacin tosylate are compounds encompassedby the present invention.

In certain embodiments the synthesis of moxifloxacin hydrochloride maybe performed as shown in FIG. 1.

With the aim of carrying out screening of solvents in which variousmoxifloxacin salts are to be prepared, with the final aim of evaluatingthe capacity thereof to purify moxifloxacin, the acids indicated in thefirst column of the table below were used.

Preparations were carried out in different alcoholic solvents, asindicated in the first line of table I.

TABLE I ACID Methanol Ethanol Isopropanol Benzylalcohol Acetic acid — —— — Formic Acid — — — — Hydrochloric acid X X X — Phosphoric Acid X X X— Oxalic Acid — — X — Succinic Acid — — — — Bromidric Acid X X X XAnhydrous Citric X — — — Acid Tartaric Acid — — — — P-toluenesulfonic XX X — Acid Methanesulfonic — X X — Acid

The “-” symbol means that there was no precipitation of moxifloxacinsalt from the tested solvent, while “X” means that the relative salt wasisolated. The experiment was conducted using 5 solvent volumes, 1.05molar equivalents of acid and carrying out the isolation of the salt byfiltration at ambient temperature.

Methods according to the present invention provide for the reduction ofthe amount of impurity of formula (VII) in moxifloxacin hydrochloridefrom up to 5% to values below 0.15%, for example, in a range of about0.05% to about 0.15%. In particular, for formula (VII) impurity contentat levels between about 1.2% and about 5% it is recommended to carry outoptional step (b) with one or more purifications of the compound offormula (IV) while for contents lower than 1.2% optional step (b) isusually not necessary. The initial moxifloxacin, obtained through theprocedure described in Example 1, normally has a formula (VII) impuritycontent ranging from about 0.8% to about 1.2% and thus typically step(b) does not need to be carried out.

Methods of the present invention can thus provide moxifloxacinhydrochloride having between about 0.05% and about 0.15% of impurity offormula (VII) and in some embodiments between about 0.06% and about0.14%, and in some embodiments between about 0.06% and about 0.09%, andin other embodiments about 0.08% of such impurity.

Step (a) may be carried out starting from a moxifloxacin base isolatedor present in solution, for example in a solution coming from thesynthesis thereof by coupling two syntons of formula (V) and (VI). Step(a) may be carried out in an organic solvent, such as a C1-C4 alcoholsuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, sec-butanol, tert-butanol. In certain embodiments it iscarried out in isopropanol. Sulfonic acid may be added in solid form orin a solution of an organic solvent, preferably in the same solvent inwhich the moxifloxacin base is solubilised.

Step (b) is optional and provides for the purification of the compoundof formula (IV) through one or more re-crystallizations or pulpingthereof in an organic solvent, with the possible addition of water. Step(b) may be carried out in an isopropanol and water mixture. In certainembodiments it is constituted by one or two pulpings. This optional stepallows for the reduction in the amount of impurity of formula (VII) andcan be conveniently used when the initial moxifloxacin has a formula(VII) impurity content greater than about 1.2% (HPLC A %).

According to the present invention step (c) may provide for the directconversion of the moxifloxacin salts of formula (IV) in moxifloxacinhydrochloride or such conversion may be carried out with the followingtwo steps:

(c1) conversion of the compound of formula (IV) in moxifloxacin base offormula (II),

(c2) salification of moxifloxacin base of formula (II) with hydrochloricacid resulting in moxifloxacin hydrochloride of formula (I).

Methods for the direct conversion of moxifloxacin salts of formula (IV)in moxifloxacin hydrochloride may be carried out in presence ofconcentrated hydrochloric acid, ethanol and water. The conversion withtwo steps may be carried out by firstly releasing moxifloxacin from thesalt thereof by extracting in an organic solvent in the presence of abase in the aqueous phase. The organic phase may be constituted by adichloromethane and isopropanol mixture, while the aqueous phase maycontain sodium bicarbonate. Subsequently the moxifloxacin base phase maybe converted into moxifloxacin hydrochloride through treatment usingconcentrated hydrochloric acid in ethanol.

A further unexpected advantage of methods according to the presentinvention is that preparing the salts of formula (IV), besides reducingthe formula (VII) impurity content, also allows increasing both thechemical purity and the optical purity of moxifloxacin.

Comparative Table II below summarises the capacity of variousmoxifloxacin salts to remove or increase the formula (VII) impuritycontent in moxifloxacin and increase the chemical purity thereof. In thefirst line data are indicated regarding the initial moxifloxacin thatwas used.

TABLE II Moxi Moxifloxacin salt Impurity (VII) Purity A %(VII) salt/Acid used in step (a) obtained HPLC A % HPLC A % A %(VII) Moxi. —Initial Moxifloxacin 1.77% 72.77% — Hydrochloric acid Hydrochloride1.54% 93.45% 87% Phosphoric Acid Phosphate 2.31% 76.34% 131%  BromidricAcid Bromohydrate 2.22% 86.75% 125%  Oxalic Acid Oxalate 1.88% 87.38%106%  — Initial Moxifloxacin 1.84% 85.64% — NaphthaleneNaphthalenedisulphate 1.85% 95.06% 100%  disulfonic acid (1:1)Naphthalene Naphthalenedisulphate 1.32% 96.12% 71% disulfonic acid (2:1)Methanesulfonic acid Methanesulfonate 0.78% 87.26% 42% EthanesulfonicAcid Ethanesulfonate 0.70% 98.52% 38% — Initial Moxifloxacin 1.09%90.27% — P-toluenesulfonic acid Tosylate 0.54% 98.64% 50% — InitialMoxifloxacin 1.38% 89.55% — P-toluenesulfonic Tosylate 0.73% 98.45% 53%acid — Initial Moxifloxacin 1.79% 91.01% — p-toluenesulfonic acidTosylate 0.82% 98.55% 46%

The initial moxifloxacin having been prepared according to methodsdescribed in U.S. patent application Ser. No. 13/051,081 owned by F.I.S.Fabbrica Italiana Sintetici S.p.A., is free of isomer-6 impurity offormula (VIII) and thus it was not possible to evaluate the advantagesderiving from methods according to the present invention with respect tosuch other typical process impurities.

The preparations of moxifloxacin salts indicated in Table II werecarried out obtaining the moxifloxacin base in isopropanol and addingthe corresponding acid in suitable amounts.

Table II shows that the salts of formula (IV) according to theembodiments of the present invention, i.e. the moxifloxacin salts withsulfonic acids, resulting in moxifloxacin having a low formula (VII)impurity content, typically between about 0.5% and about 0.9%, wellbelow the levels obtained, for example, with the moxifloxacin salt withoxalic acid, or with hydrobromic acid where the impurity even increases(see the last column with a ratio between the amount of the impurity(VII) in the prepared salt and initial one in the initial moxifloxacin).The preparation of the tosylate salt allows for the reduction of theamount of such impurity by about 50%. In certain embodiments impurity(VII) provides characteristic 1H-NMR spectra as shown in FIG. 3. Thepresent invention also provides for moxifloxacin salts of stoichiometry1 mole of naphtalenedisulfonic acid for two moles of moxifloxacin calledmoxifloxacin naphtalendisulphonate (2:1). In certain embodiments the twosulfonic groups are in position 1 and 5 on the naphthalene ring.

The preparation of moxifloxacin tosylate according to the presentinvention is especially useful. Moxifloxacin tosylate prepared accordingto embodiments of the invention provides characteristic 1H-NMR spectraas shown in FIG. 2. Moxifloxacin tosylate prepared according to suchmethods also provides a crystalline solid which exhibits acharacteristic X-Ray Powder Diffraction (XRPD) pattern withcharacteristic peaks expressed in 2-Theta value: 8.8, 10.2, 12.1, 16.7,17.0 (+/−) 0.1 (see FIG. 4). We refer to this crystalline form as FormI.

In addition, moxifloxacin tosylate shows an FT-IR spectrum having thefollowing peaks: 1717, 1626, 1446, 1239, 1155, 1031, 1009, 803 cm-1 (seeFIG. 5).

This crystalline solid has a melting point of 283° C. determined by DSC(onset) (see FIG. 6) and presents a needle-shaped crystal habit (seeFIG. 7).

Purified moxifloxacin tosylate typically has K.F.<0.10%, Loss of Drying(LOD)<0.20% (w/w), HPLC purity>99.3% (A %), N-methyl impurity of formula(VII) about 0.30% (HPLC A %) and specific optical rotation comprised inthe range of −100° to −106°.

Moxifloxacin hydrochloride prepared according to embodiments of thepresent invention does not contains ppm of genotoxic impurities such asthe C1-C4 alkyl esters of p-toluenesulphonic acid, particularly methyl,ethyl and isopropyl p-Toluenesulphonate. The same is true of thecorresponding moxifloxacin base and moxifloxacin tosylate. The GC-MSmethod employed for this determination is described in Example 7 andallows for the detection of 0.4 ppm of these potential impurities eitherin moxifloxacin salts such as the hydrochloride, tosylate, etc. ormoxifloxacin base.

The absence of C1-C4 alkyl esters of p-toluenesulphonic acid or amountslower than 10 ppm of these impurities is important for the commercialproduct since such impurities may be genotoxic and since the productshould conform to the ICH, EMA and FDA Guidelines on genotoxicimpurities. To our knowledge, these impurities have never beeninvestigated with respect to moxifloxacin and salts thereof.

It has also been surprisingly discovered that moxifloxacin tosylate is aprocess intermediate that itself may have therapeutic value, inparticular for use as an antibacterial agent which may be included inpharmaceutical compositions which also may comprise one or morepharmaceutical carries and/or excipients.

Further reduction in the amount of the N-methyl impurity of formula(VII) to values below 0.15% may be achieved in the step of preparingmoxifloxacin hydrochloride. Or, when starting from moxifloxacincontaining more than about 1.2% of impurity of formula (VII), it may beachieved in the optional purification step.

Moxifloxacin hydrochloride obtained according to the embodiments of thepresent invention, thus may comprise the impurity of formula (VII) in arange between about 0.05% and about 0.15%, in other embodiments, betweenabout 0.06% and about 0.14%, and in other embodiments between about0.06% and about 0.09%, may be conveniently used for the preparation ofpharmaceutical formulations also comprising one or more pharmaceuticallyacceptable excipients and/or carriers.

Moxifloxacin hydrochloride obtained according to the embodiments of thepresent invention thus may be used in medicine, and in particular as anantibacterial agent, given that the formula (VII) impurity contentcomplies with ICH Q3A guidelines regarding impurities inpharmaceutically active ingredients.

Methods according to embodiments of the present invention described inExample 3, provide moxifloxacin hydrochloride in anhydrous form, havingan HPLC purity equivalent to 99.80% for which all impurities are below0.10%. Accordingly, this compound is pharmaceutically acceptable.

Furthermore, the compound of formula (IV)

in which R is C1-C12 linear, or branched alkyl or is an aryl and inwhich, for example, R is chosen among C1-C4 alkyl, phenyl and tolyl canbe used in medicine, particularly for use as an antibacterial agent.Also moxifloxacin naphtalendisulphonate (2:1) may be used for the samemedical uses. Such compounds include moxifloxacin mesylate andmoxifloxacin tosylate. These compounds may be formulated inpharmaceutical compositions comprising one or more pharmaceuticalsexcipients and/or carriers. These formulations may be employed for oralor topical use (e.g. tablets and creams, respectively). For example, anoral formulation may include moxifloxacin tosylate, lactose monohydrate,microcrystalline cellulose, croscarmellose sodium, magnesium stearate,hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol.

EXAMPLES Example 1 Synthesis of Moxifloxacin Tosylate of Formula (IV,R=p-MePhenyl or Tolyl)

50.0 g of1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acidof formula (V) (1.0 mol. equiv.), 15.80 g of Mg(OH)₂ (1.6 mol. equiv.)and 300 mL of Acetonitrile were introduced into a 4-neck flask providedwith a mechanical stirrer, thermometer, cooler and thermostat. Heatingwas carried out at 78° C. for one hour under slow stirring with the aimof forming the Moxifloxacin complex with Magnesium. A solution formed by34.20 g of (4aS, 7as)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula(VI) and 150 mL of Acetonitrile was dosed in 1 hour. The reactionmixture was left at reflux for another 4 hours. Upon completing thereaction (conversion exceeding 90%) the mixture was cooled at 50° C. andthe ACN was distilled under vacuum up to obtaining a soft pasty residue.Such residue was cooled at 0° C. and a cold solution at 0° C. made up of150 mL of Acetone and 300 mL of Dichloromethane was then added slowly.Stirring was carried out for 10 minutes at room temperature then 2.5 gof dicalite and 2.5 g of acticarbone were added. Stirring was carriedout for 10 minutes then filtration was carried out on a dicalite panel.The filtrate was concentrated to dryness in the rotavapor then recoveredusing 300 mL of dichloromethane. This organic solution was washed usinga solution made up of 100 mL of a saturated NaHCO₃ solution and 50 mL ofpurified water. The underlying organic phase containing the product wasseparated and the aqueous phase was re-extracted using 100 mL ofdichloromethane. The organic phases were mixed again and then driedobtaining 71.0 g of Moxifloxacin base, with HPLC purity equivalent to90.27% and with formula (VII) impurity equivalent to 1.09%.

The solid residue was recovered using 100 mL of purified water and 800mL of Isopropanol. Heating was carried out at reflux up to completedissolution. A solution of 26.06 g of paratoluenesulfonic acid (1.1 mol.equiv.) in 100 mL of Isopropanol was dripped at 70° C. in one hour. Itwas slowly brought to 35° C., then it was left under stirring at 35° C.for one night.

The suspension was paper-filtered at 35° C. and the solid was washedusing 100 mL of Isopropanol. The solid was dried in an oven at 50° C.for at least 8 hours.

72.5 g equivalent to a 74.6% molar yield of Moxifloxacin Tosylate wereobtained as a hazelnut-coloured solid with HPLC purity equivalent to98.46% and with a formula (VII) impurity content equivalent to 0.54%.

¹H-NMR (400 MHz, DMSO-d₆): δ/ppm=0.84-1.24 (m, 4H), 1.70-1.85 (m, 4H),2.30 (s, 3H), 2.65-2.2.72 (m, 1H), 2.98-3.03 (m, 1H), 3.24-3.28 (m, 1H),3.52-3.55 (m, 1H), 3.59 (s, 3H), 3.75-3.92 (m, 3H), 4.09-4.20 (m, 2H),7.12 (d, 1H, j=7.88 Hz), 7.49 (d, 1H, j=8.04 Hz), 7.71 (d, 1H, j=14.13Hz), 8.69 (s, 1H).

-   -   Melting point=273° C. (determined using DSC).

Example 2 Purification of Moxifloxacin Tosylate of Formula (IV,R=p-MePhenyl or Tolyl)

72.5 g of Moxifloxacin Tosylate obtained in Example 1 were dispersed ina solution of 1276 ml of isopropanol and 142 ml of water. The suspensionwas heated at 80° C. for one hour, then slowly cooled for one night upto 35° C. The suspension remained at 35° C. for 2 hours, then filteringwas carried out a paper filter and washing with 142 ml of isopropanol.The solid was dried in an oven at 50° C. for at least 8 hours.

68.2 g equivalent to a 94% molar yield of purified Moxifloxacin Tosylateas a dirty white solid were obtained. The obtained Moxifloxacin Tosylatehad an HPLC purity equivalent to 99.30% (A %) with a formula (VII)impurity content equivalent to 0.27%.

Example 3 Synthesis of Moxifloxacin Hydrochloride Starting fromMoxifloxacin Tosylate of Formula (IV, R=p-Mephenyl)

68.2 g of purified moxifloxacin tosylate of example 2 (1.0 mol. Equiv.)(HPLC purity equivalent to 99.30% and impurity of formula (VII)equivalent to 0.27%), 409.2 mL of saturated NaHCO3 solution, 136.4 mL ofpurified water, 409.2 mL of dichloromethane and 68.2 mL of isopropanolwere introduced into a 4-neck flask provided with a mechanical stirrer,thermometer, cooler and thermostat. Heating was carried out at 30-35° C.and stirring was carried out for one hour up to complete dissolution.Then the phases were separated and the aqueous phase was extracted using136.4 mL of Dichloromethane. The organic phases were collected anddried. The obtained solid was recovered with 954.8 mL of Ethanol and136.4 mL of purified water. Heating was carried out at reflux up tocomplete dissolution, then it was brought to 60° C. and a solution of12.3 mL of concentrated hydrochloric acid (32%) (1.05 mol. equiv.) and136.4 mL of Ethanol was dripped in 2 hours. It was brought to r.t in 4hours, it was left at room temperature for at least 4 hours, then it wascooled at 0° C. and it was left at 0° C. for another 4 hours. Theobtained crystal was filtered washing it with 68.2 mL of Ethanol. Theobtained salt was dried at 50° C. under vacuum for 24 hours. 44.3 g ofmoxifloxacin hydrochloride with a molar yield equivalent to 85.1% withHPLC purity equivalent to 99.79% and a formula (VII) impurity contentequivalent to 0.08% was obtained. The obtained product does not contain,even at ppm level, any ester of sulfonic acids as an impurity. This isimportant because it is well-known that such impurities are genotoxic.

Example 4 Preparation of the Impurity of Formula (VII)

5 g of Moxifloxacin free base (1.0 mol. equiv.), 50 mL of methanol and3.5 g of potassium carbonate were introduced into a 3-neck flaskprovided with a mechanical stirrer, thermometer, cooler and thermostat.Cooling was carried out at 0° C. and 6 g of methyl iodide (3.4 mol.equiv.) were dripped. Stirring was carried out for one night at r.t. Thereaction was quenched by dripping 50 ml of a 10% sodium hydroxidesolution. It was left to stir for one hour and it was brought to pH=8-9with diluted hydrochloric acid. It was diluted using 200 ml of water andthe aqueous phase was washed three times using 100 ml ofdichloromethane. Precipitation was carried out by dripping 10 ml of 10%diluted hydrochloric acid, obtaining a light brown precipitate which waspaper-filtered and dried in an oven at 50° C. under vacuum. 4.6 g offormula (VII) impurity were obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ/ppm=0.86-1.11 (m, 4H), 1.44-1.55 (m, 1H),1.79-1.86 (m, 2H), 1.95-2.05 (m, 1H), 2.82-2.86 (m, 1H), 3.30 (s, 3H),3.43-3.46 (m, 1H), 3.62 (s, 3H), 3.68-3.74 (m, 2H), 3.94-3.98 (m, 1H),4.12-4.27 (m, 3H), 7.72 (d, 1H, j=13.06 Hz), 8.68 (s, 1H).

Example 5 HPLC Method for Quantifying the Moxifloxacin Purity and theFormula (VII) Impurity Content in Moxifloxacin

Chromatographic conditions:Column: Zorbax Eclipse Plus C8, 100×4.6 mm, 1.8 μm or equivalentColumn temp: 20° C.Mobile phase A: TFA 0.1% in H₂OMobile phase B: TFA 0.1% in MeOH

Time A B (min) (%) (%) Gradient: 0 60 40 5.5 40 60 12 0 100 13 0 10013.5 60 40Post-run time: 4 minutesFlow: 1.1 mL/min

Detector: UV at 306 nm

Injection volume: 2.5 μL

Dilutent: H₃PO₄ 0.1% in H₂O/ACN (7/3)

Duration of analysis: 13.5 min

Compound RT (min) RRT Impurity of formula (VII) 3.56 0.92 MOXIFLOXACIN3.86 1.00

Example 6 Synthesis of Moxifloxacin Ethanesulfonate of Formula (IV,R=et)

The procedure is repeated as in Example 1 except that ethanesulfonicacid was used instead of paratoluenesulfonic acid, in the same molarequivalents.

Ethanesulfonate moxifloxacin obtained as a dirty white solid having thefollowing 1H-NMR spectrum.

¹H-NMR (400 MHz, DMSO-d₆): δ/ppm=0.83-0.90 (m, 1H), 1.02-1.22 (m, 6H),1.67-1.1.85 (m, 4H), 2.35-2.4 (q, 2H, j=7.42 Hz), 2.63-2.70 (bs, 1H),2.95-3.00 (m, 1H), 3.22-3.25 (m, 1H), 3.51-3.58 (m, 4H), 3.74-3.92 (m,3H), 4.03-4.17 (m, 2H), 7.70 (d, 1H, j=14.17 Hz), 8.67 (s, 1H).

Example 7 GC-MS Method for the Determination of the p-ToluensulphonicAcid Alkyl Esters (Methyl, Ethyl and Isopropyl Esters) in Samples ofMoxifloxacin Tosylate, Moxifloxacin Hydrochloride and Moxifloxacin Base

Chromatographic conditions (GC Agilent 6890N-MS 5975 Quadrupole):GC Column: DB 5 (or equivalent) L=30 m ID=0.32 mm FT=0.25 μm, with 1 mprecolumn

Injector Temperature: 280° C.;

Oven Program: 70° C. for 1.5 min, 10° C./min to 200° C., 20° C./min to a300° C., 300° C. for 4 min;Injector: Splitless mode, with 1.0 min of splitless time.Carrier Gas: He, 1.8 mL/min, constant flow mode (about 8 psi at 40° C.);Detector: MS a Single Quadrupole, SIM mode;SIM Parameter: From 6.0 to 11.20 min-155 e 186 m/zFrom 11.20 to 11.75 min-155 e 200 m/zFrom 11.75 min-155 e 214 m/z(Modify the acquisition ranges based on RT of the analytes)Injection Volume: 3 uL with autosampler, slow injection;Run Time: 23.5 min;

Solvent: Toluene.

The sample of Moxifloxacine Tosylate or hydrochloride should be treatedwith NH₃(aq)/Toluene.

What is claimed is:
 1. A compound of formula (IV):

wherein R is a C1-C12 linear or branched alkyl or an aryl.
 2. Thecompound of claim 1, wherein R is selected from the group consisting of:C1-C4 alkyl, phenyl and tolyl.